Cannabinoids are compounds derived from the cannabis sativa plant commonly known as marijuana. The plant contains more than 400 chemicals and approximately 60 cannabinoids. The most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly Δ9-THC.
Currently, Δ9-tetrahydrocannabinol, also known as dronabinol, is available commercially in Marinol® soft gelatin capsules which have been approved by the Food and Drug Administration (FDA) for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation of AIDS patients suffering from the wasting syndrome. Δ9-tetrahydrocannabinol shows other biological activities, which lend themselves to possible therapeutic applications, such as in the treatment of glaucoma, migraine headaches, spasticity, anxiety, analgesia, and drug addiction.
In Marinol®, Δ9-THC is dissolved in sesame oil and encapsulated in gelatin capsules for oral administration. After oral administration, Dronabinol has an onset of action of approximately 0.5 to 1 hour, with a peak effect of 2-4 hours. The duration of action for psychoactive effects is 4-6 hours, but the appetite stimulant effect may continue for 24 hours or longer after administration. The maximal plasma levels after oral dosing of 20 mg Δ9-THC in a sesame oil formulation are around 10 ng/ml.
At the present time, some cancer patients manage to obtain prescriptions for marijuana in order to alleviate pain as well as nausea and vomiting due to chemotherapy. This latter situation arises due to poor or partial response from oral therapy, which often requires oral administration two to three times a day to obtain equivalent acute psychological and physiological effects obtained from smoking marijuana.
When administered orally, Δ9-THC or dronabinol is almost completely absorbed (90-95%) after a single oral dose. However, due to the combined effect of first pass hepatic metabolism and high lipid solubility, only about 10-20% of an administered dose reaches systemic circulation with highly variable maximal concentrations. It has been found that fasting or food deprivation may decrease the rate of absorption of Δ9-THC from the sesame oil capsules currently available in the market. Previous studies have reported that another limitation of orally administered Δ9-THC is the large inter-subject variability in absorption.
Other postulated mechanisms for the biopharmaceutical anomalies can be attributed to the physical-chemical properties of Δ9-THC. This compound is highly lipophilic, essentially water insoluble, and potentially acid labile within the stomach. This compound is also sensitive to environmental storage and stress conditions. For instance, this compound is thermolabile and photolabile, and long-term storage can lead to a cumulative decrease in Δ9-THC content by an oxidation reaction forming cannabinol (CBN).
It is well known that in mammals certain areas of the alimentary canal have a venous drainage, which does not involve a first pass through the liver. The avoidance of the first pass effect is the rationale for the use of rectal, buccal, nasal, and sublingual formulations. A Δ9-THC and cannabidiol combination has been formulated as a buccal spray. Some of the disadvantages associated with nasal, sublingual and buccal routes of administration are that the nasal mucosa may cause pain or reflex sneezing and, in extreme cases, may cause irritation and damage to the nasal mucosa. Sublingual formulations may stimulate the flow of saliva, making it difficult for patients to avoid swallowing when substantial amounts of saliva are produced. Also, buccal formulations may be subject to the same limitations as sublingual formulations.
Both sublingual and buccal formulations depend on the efficient transfer of medicament from a hydrophilic vehicle to the mucous membrane of the sublingual or buccal mucosa. Transfer of medicament through the interstices between or through epithelial cells is governed principally by the lipid solubility of the medicament. When a drug is water insoluble as in the case with cannabinoids, this presents a further barrier to absorption from the sublingual area.
In an effort to improve local drug delivery of Δ9-THC, researchers have tried to develop a transdermal delivery system. The bioactive material administered dermally, however, may show erratic and irregular absorption. Hence, the need exists for the addition of absorption enhancers which in some cases may be detrimental to the skin due to local side effects.
Other delivery systems for Δ9-THC or cannabinoids described in the patent literature, include: Metered dose inhaler using non-CFC propellants (U.S. Pat. Nos. 6,509,005 and 6,713,048); Pump action spray (U.S. Pat. No. 6,946,150); Microsphere nasal delivery system (U.S. Pat. No. 6,383,513); Water soluble prodrugs for intranasal administration (U.S. Pat. No. 6,380,175); Topical liniment (U.S. Pat. No. 6,949,582); Cyclodextrin complexes with cannabinoids (U.S. Patent Application No. 20050153931); and solid lipid compositions for oral administration (U.S. Pat. Nos. 5,891,469 and 5,989,583).
This solid lipid composition involves a method for delivering a non-psychoactive cannabinoid (i.e. dexanabinol) in a dry lipid mixture to greatly enhance oral bioavailability when compared to known formulations. With enhanced absorption characteristics of oral delivery systems, the patentees anticipated that treatment could be directed towards brain damage associated with stroke, head trauma, and cardiac arrest. This, however, required sufficient bioavailability of the drug compound. Oral Δ9-THC or dronabinol therapy would be greatly benefited by improved bioavailability for treating a variety of conditions described above.
Oral dosage forms are designed to enable sufficient availability of the active compound at its site of action. The bioavailability of a drug depends on several parameters, i.e., the physicochemical nature of the active compound, the dosage form, as well as physiological factors. The cannabinoid compounds, being hydrophobic by nature, show wetting difficulties and poor dissolution in the gastrointestinal region. In addition, Δ9-THC or dronabinol undergo extensive hepatic first-pass metabolism. These properties represent barriers to drug absorption from oral dosage forms. These barriers in turn cause a subsequent reduction in the bioavailability.
To compensate for the poor absorption displayed by many drugs, a pharmaceutical formulation may utilize or take advantage of one or more mechanisms to increase the rate and/or the extent to which the administered drug is absorbed.
Dronabinol or Δ9-THC belongs to Class II (low aqueous solubility and high permeability) of the biopharmaceutical classification system (BCS). Hence, there may be an advantage associated with a self-emulsifying (SEDDS) lipid based delivery system to enhance the dissolution of a drug system in an aqueous environment. Patents demonstrating the potential use of SEDDS or lipid delivery systems for lipophilic drugs are U.S. Pat. Nos. 5,484,801; 5,798,333; 5,965,160; 6,008,228; 6,730,330. See also U.S. Patent Application No. 20050209345, and International Application No. PCT/EP96/02431 (WO 96/39142)).
There are no known reports disclosing the oral delivery of Δ9-THC based on SEDDS technology to improve the dissolution characteristics and to increase the oral bioavailability through chylomicron/lipoprotein assembly for subsequent transport through the lymphatic system. Δ9-THC dosage forms intended for other routes of administration are subjected to high intra and inter patient variability.
However, SEDDS systems have not been used with cannabinoids for a number of reasons; first, due to the possibility that the SEDDS system may undergo gastric emptying while in a colloidal state; second, or the emulsifying system may result in rapid absorption and higher peak concentrations of the drug; third, large concentrations of surfactant in the SEDDS system may cause gastrointestinal irritation.
Therefore, one of the objects of the present invention is to provide a more optimized and improved delivery system for Δ9-THC to meet the desired needs of the patients.
It is still another object of the present invention to provide an oral dosage form of Δ9-THC or dronabinol, which provides sufficient bioavailability of this drug for the treatment of numerous medical complications for which the drug can be therapeutically beneficial (e.g. brain damage associated with stroke, heat trauma, and cardiac arrest).
It is another object of the present invention to provide a pharmaceutical formulation which compensates for poor absorption displayed by Δ9-THC or dronabinol.
It is yet another object of the present invention to provide a pharmaceutical formulation for Δ9-THC or dronabinol which does not result in gastric emptying while in a colloidal state.
It is another object of the present invention is to provide a pharmaceutical formulation for Δ9-THC or dronabinol which does not cause gastrointestinal irritation.
Another object of the present invention is to promote drug absorption through alternate gastrointestinal pathways, outside the conventional hepatic portal vein transport mechanism, which results in a high first-pass effect.